April 2016 Edition Vol.11, Issue 4

Why Histology Matters in Lung Cancer Treatment: Updates from the Annual Winter Lung Cancer Conference

Why Histology Matters in Lung Cancer Treatment: Updates from the Annual Winter Lung Cancer Conference

By Adrian K. Barfield

Given the increase in new agents for the various histologies of lung cancer and the use of direct-to-consumer marketing, it is more important than ever for clinicians to be provided insight to assist in making more informed treatment decisions.  The 13th Annual Winter Lung Cancer Conference, in Miami, Florida, hosted by Research to Practice and co-chaired by Dr. Mark Socinski, Dr. Rogerio Lilenbaum and Dr. Neil Love, was well attended and provided excellent guidance for practicing clinicians.  Of particular interest were sessions related to the immune checkpoint inhibitors and management of metastatic lung cancers that have no identifiable targetable mutations.

During the management of metastatic disease with no identifiable tumor mutations session, moderator Mark A. Socinski, MD, University of Pittsburgh, Pittsburg, Pennsylvania, said that using histology for therapeutic decision making requires “a high level of confidence that you know what the histology is,” adding that it is important to realize the diagnostic accuracy in lung cancer is influenced by the type of biopsy procedure, the quality of tumor in the specimen, the degree of tumor differentiation, the use of ancillary studies, and the experience of the pathologist.

He noted that if tissue from an initial biopsy is insufficient for molecular testing, a second biopsy could be requested. With “classic” histopathologic findings, special staining may not be necessary and the tumor tissue can be sent for molecular testing. However, poorly differentiated tumors present a diagnostic challenge, and selective special staining can be helpful, as can a second pathologic opinion. When there is uncertainty about the pathology of tumor tissue, clinical factors, such as age, performance status, smoking history, and co-morbidities, may be used to guide therapeutic choices.

What the Clinical Trials Reveal

Detailing 5 clinical trials in non-small cell lung cancer (NSCLC), Dr. Socinski described why histology matters when selecting or avoiding specific therapeutic options. For instance, in the Phase 2 trial of carboplatin and paclitaxel with and without bevacizumab in patients with NSCLC, major bleeding events were associated with squamous cell morphology in patients receiving bevacizumab.1 This trial “changed the life of pathologists,” because rather than just distinguishing small-cell lung cancer from non-small cell, they now had to distinguish squamous from non-squamous histology.

In the first prospective Phase 3 study in NSCLC that reported survival differences between platinum doublets according to histology, the pemetrexed/cisplatin (P/C) combination showed a significant survival difference vs gemcitabine/cisplatin (G/C) in 2 histologic groups: patients with adenocarcinoma and patients with large-cell carcinoma. Conversely, in patients with squamous cell histology, the G/C arm showed significant improvement in survival vs the P/C arm.2

Molecular testing for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in adenocarcinoma and selected squamous-cell lung cancers to guide therapy with tyrosine kinase inhibitors (TKI) is now standard of care.3 Dr. Socinski said that patient clinical or risk factors, including smoking status, are irrelevant. “It’s all about pathology” regarding testing, which should be done at the time of diagnosis as well as after treatment with a targeted therapy.

In a nab-paclitaxel plus carboplatin study, the better overall response rate seen in that treatment arm vs solvent-based paclitaxel in patients with squamous cell lung cancer was called an “unanticipated” result.4 Although it didn’t translate into a progression-free survival or overall survival benefit, the study was not powered to look at squamous histology. Dr. Socinski said, “Every patient with squamous histology I see is symptomatic and the best way to improve their symptoms is to shrink their tumor. This offers them an advantage in this setting.”

Finally, in the SQUIRE Phase 3 trial of gemcitabine and cisplatin with and without necitumumab as first-line therapy in patients with stage IV squamous NSCLC, overall survival was improved by the addition of necitumumab to standard doublet chemotherapy.5

Treating Strategies in Elderly Patients with NSCLC

When it comes to treatment strategies in elderly patients with NSCLC, Rogerio Lilenbaum, MD, Yale Cancer Center, New Haven, Connecticut, pointed out that in American Society of Clinical Oncology (ASCO) guidelines, chemotherapy options should not be selected or altered on the basis of age alone for elderly patients with stage IV NSCLC.6 Although elderly patients may experience increased survival when treated with doublet vs single agent therapy, it may come at the cost of increased risk of chemotherapy-related toxic death.7 Therefore, there needs to be a way to decide which elderly patients are candidates for doublet or single agent chemotherapy, and who might benefit from best supportive care.

Dr. Lilenbaum described a study that used a comprehensive geriatric assessment (CGA) tool to guide treatment decisions in patients at least age 70 years with stage IV NSCLC.8 In one arm, physicians made therapy decisions using age and performance status. In the other arm, CGA was used to allocate patients to one of 3 groups: fit, which received combination chemotherapy; vulnerable, which received single agent therapy; or frail, which received best supportive care. The primary endpoint was treatment failure-free survival, which is important because it captures toxicity-related issues.

Treatment allocation based on CGA did not improve treatment-failure free survival or overall survival, but did somewhat reduce toxicity. Dr. Lilenbaum believes that the CGA did identify more patients for whom combination chemotherapy was appropriate; median survival was much lower for patients receiving only supportive care even though median survival for the intent-to-treat population was similar between the 2 arms. Grand rounds to put this study into clinical context have also been published.9

Immune Checkpoint Inhibitors in Second-Line NSCLC

Immune checkpoint inhibitors have made a big splash in the second-line NSCLC marketplace, partially fueled by a significant increase in direct-to-consumer advertising. However, there appears to be a significant benefit for select patients whose first-line therapy has failed. Given the range of options available, it is extremely important to understand which patients will benefit from immune checkpoint inhibitors versus other targeted therapies. Second-line agents given for advanced or recurrent NSCLC are listed in Table 1.

Table 1.  FDA-Approved Second-Line or Post Platinum Therapy Treatments for Stage IV NSCLC or Recurrent Disease

Suresh S. Ramalingam, MD, Emory University, Atlanta, Georgia, reviewed the basics of immunotherapy in cancer, focusing on the roles of programmed death-1 (PD-1) and its ligand, PD-L1, in lung cancer. PD-L1 secreted by tumor cells, binds to PD-1 receptors on T cells and prevents them from attacking the tumor. Agents that inhibit PD-L1 allow the immune system to target the tumor. In addition to PD-1, other T cell immune checkpoint inhibitory and activating receptors are of interest for cancer therapy. A greater understanding of how conventional therapies, such as chemotherapy and radiation, affect the immune system should help clarify how checkpoint inhibitors can best be combined with other therapies.

The two approved immune checkpoint inhibitors, nivolumab and pembrolizumab, have associated PD-L1 assays, and PD-L1 expression is being studied for checkpoint inhibitors in development (Table 2).

Table 2. Immune Checkpoint Inhibitors and PD-L1 Assays

Dr. Ramalingam thinks that PD-L1 should not be considered a biomarker because responses have been seen in patients whose tumors are PD-L1 negative or have low levels of expression. Each agent has its own companion diagnostic and cutoff levels of expression. “We need to reconcile these before we can make sense across drugs for biomarkers,” he said. There is a potential for sampling error in core biopsies because PD-L1 expression is heterogeneous in tumor regions, making it “less than an ideal biomarker,” concluding, “in the area of biomarkers we have a lot to learn.”

David R. Spiegel, MD, Sarah Cannon Research Institute, Nashville, Tennessee, discussed immunotherapy with immune checkpoint inhibitors in adenocarcinoma. He noted that although overall survival is better in patients whose tumors express PD-L1 who are treated with pembrolizumab compared with chemotherapy, for all immune checkpoint therapies some patients with PD-1 or PD-L1 negative tumors will have a response, although they may not do as well as those with positive expression.

On the other hand, there are reports from small numbers of patients that those with lung cancer having targetable mutations like EGFR and ALK will not do as well with immunotherapy. A trial of durvalumab combined with a TKI that targeted the T790M mutation in the EGFR in NSCLC patients previously treated with EGFR TKI therapy had to be suspended because of an increase in interstitial lung disease-like toxicity. “So that is something that we worry about obviously with EGFR TKIs. It seems like they would work well together, but there may be toxicities we have not anticipated. So more to come on that,” said Dr. Spiegel.

Currently, large, ongoing Phase 3 trials of checkpoint inhibitors in patients with NSCLC in combination with other checkpoint inhibitors and chemotherapies are being conducted. Dr. Spiegel said it was encouraging that immunotherapy might add to chemotherapy in the front-line setting for patients with non-squamous NSCLC. “I think all of us expect in the next 12 months we’ll have an early read on one of these combination trials, probably nivolumab in the first-line setting.”

Looking Ahead

As treatment options for lung cancer continue to be developed, unanswered questions remain. These include identifying the best treatments for histologic subtypes, determining the best ways to predict tumor response, and identifying more predictive biomarkers. Determining the best treatments for patient subpopulations, such as the elderly, remains a challenge, as does whether or not to use immune checkpoint inhibitors in patients with autoimmune conditions and how best to use the newer drugs in combination with chemotherapies that have been the backbone of lung cancer treatment. One thing that is certain, despite the clinical evidence and the rapid uptake of nivolumab in second-line treatment of NSCLC, drug companies will have to quickly sort through the relevant impact of direct-to-consumer advertising and whether or not the benefit is worth the significantly increased cost.


About the Contributor

Adrian Barfield is the President of Medallion Healthcare, an oncology focused strategic and creative agency based in Dallas, Texas. He is a guest writer for OBR and can be contacted at adrian@obroncology.com.



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  7. Quoix E, Zalcman G, Oster J-P, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011;378:1079-1088.
  8. Corre R, Greillier L, Le Caer H, et al. Use of a comprehensive geriatric assessment for the management of elderly patients with advanced non-small-cell lung cancer: the phase III randomized ESOGIA-GFPC-GECP 08-02 study. J Clin Oncol. Published online ahead of print, February 16, 2016.
  9. Presley CJ, Gross CP, Lilenbaum RC. Optimizing treatment risk and benefit for elderly patients with advanced non-small-cell lung cancer: the right treatment for the right patient. J Clin Oncol. Published ahead of print, March 21, 2016.


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